Abstract
Myotonia congenita (MC) is an inherited muscle disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. Both recessive (Becker’s disease) or dominant (Thomsen’s disease) MC are caused by mutations in the CLCN1 gene encoding the voltage-dependent chloride ClC-1 channel, which is quite exclusively expressed in skeletal muscle. More than 200 CLCN1 mutations have been associated with MC. We provide herein a detailed clinical, molecular, and functional evaluation of four patients with recessive MC belonging to three different families. Four CLCN1 variants were identified, three of which have never been characterized. The c.244A>G (p.T82A) and c.1357C>T (p.R453W) variants were each associated in compound heterozygosity with c.568GG>TC (p.G190S), for which pathogenicity is already known. The new c.809G>T (p.G270V) variant was found in the homozygous state. Patch-clamp studies of ClC-1 mutants expressed in tsA201 cells confirmed the pathogenicity of p.G270V, which greatly shifts the voltage dependence of channel activation toward positive potentials. Conversely, the mechanisms by which p.T82A and p.R453W cause the disease remained elusive, as the mutated channels behave similarly to WT. The results also suggest that p.G190S does not exert dominant-negative effects on other mutated ClC-1 subunits. Moreover, we performed a RT-PCR quantification of selected ion channels transcripts in muscle biopsies of two patients. The results suggest gene expression alteration of sodium and potassium channel subunits in myotonic muscles; if confirmed, such analysis may pave the way toward a better understanding of disease phenotype and a possible identification of new therapeutic options.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-015-8356-8) contains supplementary material, which is available to authorized users.
Highlights
Clinical myotonia impairs muscle relaxation after voluntary intense contraction
Myotonia congenita (MC) is an inherited muscle disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness
Both recessive (Becker’s disease) or dominant (Thomsen’s disease) MC are caused by mutations in the CLCN1 gene encoding the voltage-dependent chloride ClC-1 channel, which is quite exclusively expressed in skeletal muscle
Summary
Myotonia congenita (MC) is an inherited myotonia due to mutations in the CLCN1 gene encoding the skeletal muscle ClC-1 chloride channel (Koch et al 1992; George et al 1993). Loss-of-function mutations of ClC-1 channel reduce the sarcolemmal chloride conductance, which, in turn, increases sarcolemma excitability and causes a delayed relaxation manifesting as a clinical and electrical myotonia (Imbrici et al 2015). TMC often has a wider range of presentations, including subclinical to moderately severe forms. These two entities may be distinguished by inheritance pattern, age at onset, and phenotype (Lossin and George 2008; Heatwole et al 2013)
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